Practice Essentials

Iron deficiency anemia develops when body stores of iron drop too low to support normal red blood cell (RBC) production. Inadequate dietary iron, iron absorption, bleeding, or loss of body iron in the urine may be the cause.

Essential update: ACP releases new recommendations for iron deficiency anemia
he !merican College of "hysicians (!C") recently released the following treatment guidelines for adult patients with anemia and iron deficiency#$% &

! restrictive red blood cell transfusion strategy is recommended for hospitali'ed patients with coronary heart disease, with the trigger hemoglobin threshold lowered to ()* g+d, (recommendation& wea-. quality of evidence& low) /rythropoiesis)stimulating agents are not recommended for patients with mild to moderate anemia and either congestive heart failure or coronary heart disease (recommendation& strong. quality of evidence& moderate)

Signs and symptoms

"atients with iron deficiency anemia may report the following&

0atigue and diminished capability to perform hard labor ,eg cramps on climbing stairs Craving ice (in some cases, cold celery or other cold vegetables) to suc- or chew "oor scholastic performance Cold intolerance Reduced resistance to infection !ltered behavior (eg, attention deficit disorder) 1ysphagia with solid foods (from esophageal webbing) 2orsened symptoms of comorbid cardiac or pulmonary disease

0indings on physical e3amination may include the following&

Impaired growth in infants "allor of the mucous membranes (a nonspecific finding) 4poon)shaped nails (-oilonychia) ! glossy tongue, with atrophy of the lingual papillae 0issures at the corners of the mouth (angular stomatitis) 4plenomegaly (in severe, persistent, untreated cases) "seudotumor cerebri (a rare finding in severe cases)

4ee Clinical "resentation for more detail.

Diagnosis
5seful tests include the following&

Complete blood count "eripheral blood smear 4erum iron, total iron)binding capacity ( IBC), and serum ferritin /valuation for hemosiderinuria, hemoglobinuria, and pulmonary hemosiderosis 6emoglobin electrophoresis and measurement of hemoglobin !7 and fetal hemoglobin Reticulocyte hemoglobin content

ests useful for establishing the etiology of iron deficiency anemia and e3cluding or establishing a diagnosis of another microcytic anemia include the following&

4tool testing Incubated osmotic fragility testing 8easurement of lead in tissue Bone marrow aspiration

CBC results in iron deficiency anemia include the following&

,ow mean corpuscular volume (8C9) ,ow mean corpuscular hemoglobin concentration (8C6C) /levated platelet count (:;<=,===+>,) in many cases ?ormal or elevated white blood cell count

"eripheral smear results in iron deficiency anemia are as follows&

RBCs are microcytic and hypochromic in chronic cases "latelets usually are increased In contrast to thalassemia, target cells are usually not present, and anisocytosis and poi-ilocytosis are not mar-ed In contrast to hemoglobin C disorders, intraerythrocytic crystals are not seen

Results of iron studies are as follows&

,ow serum iron and ferritin levels with an elevated IBC are diagnostic of iron deficiency ! normal serum ferritin can be seen in patients who are deficient in iron and have coe3istent diseases (eg, hepatitis or anemia of chronic disorders)

4ee 2or-up for more detail.

Management

reatment of iron deficiency anemia consists of correcting the underlying etiology and replenishing iron stores. Iron therapy is as follows&

@ral ferrous iron salts are the most economical and effective form 0errous sulfate is the most commonly used iron salt Better absorption and lower morbidity have been claimed for other iron salts o3icity is generally proportional to the amount of iron available for absorption Reserve parenteral iron for patients who are either unable to absorb oral iron or who have increasing anemia despite adequate doses of oral iron Reserve transfusion of pac-ed RBCs for patients who are e3periencing significant acute bleeding or are in danger of hypo3ia and+or coronary insufficiency

4ee reatment and 8edication for more detail.

Image library

! (=)year)old man who is ; years post)2hipple surgery for pancreatic adenocarcinoma had been in good health with no evidence of recurrence until he had a maroon)colored stool that was heme positive. "hysical e3amination was unrevealing. ,aboratory study values showed a 2BC of A=== cells+>,, a hemoglobin of $$.< g+d,, a mean corpuscular volume (8C9) of A< f,, a mean corpuscular hemoglobin concentration (8C6C) of B; g+d,, a platelet count of 7<=,=== cells+>,, a creatinine level of =.A mg+d,, a B5? level of 7( mg+d,, a total bilirubin level of =.; mg+d,, a serum iron level of $C= >g+d,, a total iron)binding capacity ( IBC) of 7*= >g+d,, and a ferritin level of *< ng+m,. ! peripheral smear is shown.

Pathophysiology
Iron is vital for all living organisms because it is essential for multiple metabolic processes, including o3ygen transport, 1?! synthesis, and electron transport. Iron equilibrium in the body is regulated carefully to ensure that sufficient iron is absorbed in order to compensate for body losses of iron (see the image below). 2hereas body loss of iron quantitatively is as important as absorption in terms of maintaining iron equilibrium, it is a more passive process than absorption.

he total body iron in a (=)-g man is about ; g. his is maintained by a balance between absorption and body losses. !lthough the body only absorbs $ mg daily to maintain equilibrium, the internal requirement for iron is greater (7=)7< mg). !n erythrocyte has a lifespan of $7= days so that =.*D of red blood cells are destroyed and replaced each day. ! man with < , of blood volume has 7.< g of iron incorporated into the hemoglobin, with a daily turnover of 7= mg for hemoglobin synthesis and degradation and another < mg for other requirements. 8ost of this iron passes through the plasma for reutili'ation. Iron in e3cess of these requirements is deposited in body stores as ferritin or hemosiderin. In healthy people, the body concentration of iron (appro3imately C= parts per million #ppm%) is regulated carefully by absorptive cells in the pro3imal small intestine, which alter iron absorption to match body losses of iron (see the image below). "ersistent errors in iron balance lead to either iron deficiency anemia or hemosiderosis. Both are disorders with potential adverse consequences.

8ucosal cells in the pro3imal small intestine mediate iron absorption. Intestinal cells are born in the crypts of ,ieber-uhn and migrate to the tips of the villi. he cells are sloughed into the intestinal lumen at the end of their 7) to B)day lifespan. !bsorptive cells remain attuned to the body requirement for iron by incorporating proportionate quantities of body iron into the absorptive cells. his iron and recently absorbed iron decrease upta-e of iron from the gut lumen by satiation of iron) binding proteins with iron, by stimulating an iron regulatory element, or both. he incorporation of iron into these cells in quantities proportional to body stores of iron also provides a limited method of increasing iron e3cretion in individuals replete in iron.

/ither diminished absorbable dietary iron or e3cessive loss of body iron can cause iron deficiency. 1iminished absorption usually is due to an insufficient inta-e of dietary iron in an absorbable form. 6emorrhage is the most common cause of e3cessive loss of body iron, but it can occur with hemoglobinuria from intravascular hemolysis. 8alabsorption of iron is relatively uncommon in the absence of small bowel disease (sprue, celiac disease, regional enteritis) or previous EI surgery. Iron upta-e in the pro3imal small bowel occurs by B separate pathways (see the image below). hese are the heme pathway and 7 distinct pathways for ferric and ferrous iron.

hree pathways e3ist in enterocytes for upta-e of food iron. In the 5nited 4tates and /urope, most absorbed iron is derived from heme. 6eme is digested en'ymatically free of globin and enters the enterocyte as a metalloporphyrin. 2ithin the cell iron is released from heme by heme o3ygenase to pass into the body as inorganic iron. 8ost dietary inorganic iron is ferric iron. his can enter the absorptive cell via the integrin)mobilferrin pathway (I8").4ome dietary iron is reduced in the gut lumen and enters the absorptive cell via the divalent metal transporter)$ (18 )$+1C ) $+?ramp)7). he proteins of both pathways interact within the enterocyte with paraferritin, a large protein comple3 capable of ferrireduction. /3cess iron is stored as ferritin to protect the cell from o3idative damage. Iron leaves the cell to enter plasma facilitated by ferroportin and hephaestin, which associate with an apotransferrin receptor. he enterocyte is informed of body requirements for iron by transporting iron from plasma into the cell using a holotransferrin receptor. In ?orth !merica and /urope, one third of dietary iron is heme iron, but two thirds of body iron is derived from dietary myoglobin and hemoglobin. 6eme iron is not chelated and precipitated by numerous dietary constituent that render nonheme iron nonabsorbable (see the image below), such as phytates, phosphates, tannates, o3alates, and carbonates. 6eme is maintained soluble and available for absorption by globin degradation products produced by pancreatic en'ymes. 6eme iron and nonheme iron are absorbed into the enterocyte noncompetitively.

1ietary iron contains both heme and nonheme iron. Both chemical forms are absorbed noncompetitively into duodenal and FeFunal mucosal cells. 8any of the factors that alter the absorption of nonheme iron have little effect upon the absorption of heme iron because of the differences in their chemical structures. Iron is released from heme within the intestinal absorptive cell by heme o3ygenase and then transferred into the body as nonheme iron. 0actors affecting various stages of iron absorption are shown in this diagram. he simplest model of iron absorption must consider intraluminal, mucosal, and corporeal factors. 6eme enters the cell as an intact metalloporphyrin, presumably by a vesicular mechanism. It is degraded within the enterocyte by heme o3ygenase with release of iron so that it traverses the basolateral cell membrane in competition with nonheme iron to bind transferrin in the plasma. 0erric iron utili'es a different pathway to enter cells than ferrous iron. his was shown by competitive inhibition studies, the use of bloc-ing antibodies against divalent metal transporter)$ (18 )$) and betaB)integrin, and transfection e3periments using 18 )$ 1?!. his research indicated that ferric iron utili'es betaB)integrin and mobilferrin, while ferrous iron uses 18 )$ to enter cells. 2hich pathway transports most nonheme iron in humans is not -nown. 8ost nonheme dietary iron is ferric iron. Iron absorption in mice and rats may involve more ferrous iron because they e3crete moderate quantities of ascorbate in intestinal secretions. 6umans, however, are a scorbutic species and are unable to synthesi'e ascorbate to reduce ferric iron. @ther proteins appear to be related to iron absorption. hese are stimulators of iron transport (40 ), which are reported to increase the absorption of both ferric and ferrous iron, and hephaestin, which is postulated to be important in the transfer of iron from enterocytes into the plasma. he relationships and interactions among the newly described proteins are not -nown at this time and are being e3plored in a number of laboratories. he iron concentration within enterocytes varies directly with the bodyGs requirement for iron. !bsorptive cells of iron)deficient humans and animals contain little stainable iron, whereas those of subFects who are replete in iron contain significantly higher amounts. 5ntreated phenotypic hemochromatosis creates little stainable iron in the enterocyte, similar to iron deficiency. Iron within the enterocyte may operate by up)regulation of a receptor, saturation of an iron)binding protein, or both.

In contrast to findings in iron deficiency, enhanced erythropoiesis, or hypo3ia, endoto3in rapidly diminishes iron absorption without altering enterocyte iron concentration. his suggests that endoto3in and, perhaps, cyto-ines alter iron absorption by a different mechanism. his is the effect of hepcidin and the balance of hepcidin versus erythropoietin. 8ost iron delivered to nonintestinal cells is bound to transferrin. ransferrin iron is delivered into nonintestinal cells via 7 pathways& the classical transferrin receptor pathway (high affinity, low capacity) and the pathway independent of the transferrin receptor (low affinity, high capacity). @therwise, the nonsaturability of transferrin binding to cells cannot be e3plained. In the classical transferrin pathway, the transferrin iron comple3 enters the cell within an endosome. !cidification of the endosome releases the iron from transferrin so that it can enter the cell. he apotransferrin is delivered by the endosome to the plasma for reutili'ation. he method by which the transferrin receptorHindependent pathway delivers iron to the cell is not -nown. ?onintestinal cells also possess the mobilferrin integrin and 18 )$ pathways. heir function in the absence of an iron)saturated transferrin is uncertain. however, their presence in nonintestinal cells suggests that they may participate in intracellular functions in addition to their capability to facilitate cellular upta-e of iron.

Etiology
Dietary factors
8eat provides a source of heme iron, which is less affected by the dietary constituents that mar-edly diminish bioavailability than nonheme iron is. he prevalence of iron deficiency anemia is low in geographic areas where meat is an important constituent of the diet. In areas where meat is sparse, iron deficiency is commonplace. 4ubstances that diminish the absorption of ferrous and ferric iron include phytates, o3alates, phosphates, carbonates, and tannates (see the image below). hese substances have little effect upon the absorption of heme iron. 4imilarly, ascorbic acid increases the absorption of ferric and ferrous iron and has little effect upon the absorption of heme iron.

Both nonheme iron and heme iron have C coordinating bonds. however, ; of the bonds in heme bind pyrroles, ma-ing them unavailable for chelation by other compounds. herefore, ascorbic acid chelates nonheme iron to enhance absorption but has no effect upon heme iron. 8any dietary components, such as

phytates, phosphates, o3alates, and tannates, bind nonheme iron to decrease nonheme iron absorption. hey do not affect heme. his e3plains why heme is so effectively absorbed with foods containing these chelators. Iron hemoglobin structure. "urified heme is absorbed poorly because heme polymeri'es into macromolecules. Elobin degradation products diminish heme polymeri'ation, ma-ing it more available for absorption. hey also increase the absorption of nonheme iron because the peptides from degraded globin bind the iron to prevent both precipitation and polymeri'ation. thus, absorption of the iron in spinach is increased when the spinach eaten with meat. 6eme and nonheme iron upta-e by intestinal absorptive cells is noncompetitive.

Hemorrhage
Bleeding for any reason produces iron depletion. If sufficient blood loss occurs, iron deficiency anemia ensues (see the image below). ! single sudden loss of blood produces a posthemorrhagic anemia that is normocytic. he bone marrow is stimulated to increase production of hemoglobin, thereby depleting iron in body stores. @nce they are depleted, hemoglobin synthesis is impaired and microcytic hypochromic erythrocytes are produced.

4equential changes in laboratory values following blood loss are depicted. ! healthy human was bled < , in <==)m, increments over ;< days. ! moderate anemia ensued, initially with normal cellular indices and serum iron. 4ubsequently, the mean corpuscular volume (8C9) increased as iron was mobili'ed from body stores and reticulocytosis occurred. he serum iron decreased, followed by an increase in the total iron)binding capacity. Eradual decreases in the red blood cell indices occurred, with ma3imal microcytosis and hypochromia present $7= days after bleeding. 9alues returned to normal appro3imately 7<= days after blood loss. !t the end of the e3periment, iron was absent from body stores (marrow) because hemoglobin has a first priority for iron. Iron)<A absorption was increased after all values returned to normal in order to replenish the body store with iron. his suggests that the serum iron, total iron) binding capacity, hemoglobin concentration, and indices were not the primary regulators of iron absorption. 8a3imal changes in the red blood cell (RBC) cellular indices occur in appro3imately $7= days, at a time when all normal erythrocytes produced prior to the hemorrhage are replaced by microcytes. Before this time, the peripheral smear shows a dimorphic population of erythrocytes, normocytic cells produced before bleeding, and microcytic cells produced after bleeding. his is reflected in the red blood cell distribution width

(R12). thus, the earliest evidence of the development of an iron)deficient erythropoiesis is seen in the peripheral smear, in the form of increased R12.

Hemosiderinuria hemoglobinuria and pulmonary hemosiderosis

Iron deficiency anemia can occur from loss of body iron in the urine. If a freshly obtained urine specimen appears bloody but contains no red blood cells, suspect hemoglobinuria. @btain confirmation in the laboratory that the pigment is hemoglobin and not myoglobin. his can be accomplished easily because C=D ammonium sulfate precipitates hemoglobin but not myoglobin. 6emoglobinuria classically is ascribed to paro3ysmal nocturnal hemoglobinuria, but it can occur with any bris- intravascular hemolytic anemia. In the early days of heart surgery with implantation of artificial valves, this mechanism of producing iron deficiency anemia was commonplace in large university hospitals. oday, with better prostheses, it has become a less frequent clinical problem. 2ith less severe hemolytic disorders, there may be no significant hemoglobinuria. Investigate renal loss of iron by staining the urine sediment for iron. 6emosiderin is detected intracellularly. 8ost of these patients have a low or absent plasma haptoglobin. 4imilarly, pulmonary hemosiderosis can result in sufficient loss of iron as hemosiderin from the lungs.

Malabsorption of iron
"rolonged achlorhydria may produce iron deficiency because acidic conditions are required to release ferric iron from food. hen, it can be chelated with mucins and other substances (eg, amino acids, sugars, amino acids, or amides) to -eep it soluble and available for absorption in the more al-aline duodenum. 4tarch and clay eating produce malabsorption of iron and iron deficiency anemia. 4pecific inquiry is required to elicit a history of either starch or clay eating because patients do not volunteer the information. /3tensive surgical removal of the pro3imal small bowel or chronic diseases (eg, untreated sprue or celiac syndrome) can diminish iron absorption. Rarely, patients with no history of malabsorption have iron deficiency anemia and fail to respond to oral iron therapy. 8ost merely are noncompliant with therapy. Before placing these patients on parenteral therapy, document iron malabsorption either by measuring absorption of radioiron or by obtaining a baseline fasting serum)iron concentration and repeating the test B= minutes and $ hour after administration of a freshly prepared oral solution of ferrous sulfate (<=)C= mg of iron) under observation. he serum iron should increase by <=D over the fasting specimen.

Eenetic abnormalities producing iron deficiency have been shown in rodents (se3)lin-ed anemia #sla% mice, microcytic anemia #m-% mice, Belgrade rat). his phenomenon has not been clearly demonstrated in humans. if it e3ists, it is probably an uncommon cause of iron deficiency anemia.

!ac"ground
Iron deficiency is defined as a decreased total iron body content. Iron deficiency anemia occurs when iron deficiency is severe enough to diminish erythropoiesis and cause the development of anemia. Iron deficiency is the most prevalent single deficiency state on a worldwide basis. It is important economically because it diminishes the capability of individuals who are affected to perform physical labor, and it diminishes both growth and learning in children. "osthemorrhagic anemia is discussed in this article because it is an important cause of iron deficiency. he acute and potentially catastrophic problems of hypo3ia and shocthat can occur from significant hemorrhage or severe iron deficiency are discussed elsewhere. however, daily blood losses can be small and may be overloo-ed. @ccasionally, patients with severe iron deficiency anemia from slow but persistent gastrointestinal (EI) bleeding have repeatedly negative testing of stool for hemoglobin. herefore, it is important for the clinician to be aware of characteristics of the anemia at all intervals after the onset of bleeding. Eo to !nemia, 4ideroblastic !nemias, and Chronic !nemia for complete information on these topics.

Epidemiology
#nited States statistics
In ?orth !merica and /urope, iron deficiency is most common in women of childbearing age and as a manifestation of hemorrhage. Iron deficiency caused solely by diet is uncommon in adults in countries where meat is an important part of the diet. 1epending upon the criteria used for the diagnosis of iron deficiency, appro3imately ;)*D of premenopausal women are iron deficient. In men and postmenopausal women, iron deficiency is uncommon in the absence of bleeding.

International statistics
In countries where little meat is in the diet, iron deficiency anemia is C)* times more prevalent than in ?orth !merica and /urope. his occurs despite consumption of a diet that contains an equivalent amount of total dietary iron. the reason is that heme iron is absorbed better from the diet than nonheme iron. In certain geographic areas, intestinal parasites, particularly hoo-worm, worsen the iron deficiency because of blood loss from

the EI tract. !nemia is more profound among children and premenopausal women in these environs.

Age$related demographics
6ealthy newborn infants have a total body iron of 7<= mg (*= ppm), which is obtained from maternal sources. his decreases to appro3imately C= ppm in the first C months of life, while the baby consumes an iron)deficient mil- diet. Infants consuming cow milhave a greater incidence of iron deficiency because bovine mil- has a higher concentration of calcium, which competes with iron for absorption. 4ubsequently, growing children must obtain appro3imately =.< mg more iron daily than is lost in order to maintain a normal body concentration of C= ppm. 1uring adult life, equilibrium between body loss and gain is maintained. Children are more li-ely to develop iron deficiency anemia. In certain geographic areas, hoo-worm adds to the problem. Children are more li-ely to wal- in soil without shoes and develop heavy infestations. 1uring childbearing years, women have a high incidence of iron deficiency anemia because of iron losses sustained with pregnancies and menses. Eastrointestinal neoplasms become increasingly more prevalent with each decade of life. hey frequently present with EI bleeding that may remain occult for long intervals before it is detected. 5sually, bleeding from neoplasms in other organs is not occult, prompting the patient to see- medical attention before developing severe iron depletion. Investigate the etiology of the iron deficiency anemia to evaluate for a neoplasm.

Se%$related demographics
!n adult male absorbs and loses about $ mg of iron from a diet containing $=)7= mg daily. 1uring childbearing years, an adult female loses an average of 7 mg of iron daily and must absorb a similar quantity of iron in order to maintain equilibrium. Because the average woman eats less than the average man does, she must be more than twice as efficient in absorbing dietary iron in order to maintain equilibrium and avoid developing iron deficiency anemia. 6ealthy males lose body iron in sloughed epithelium, in secretions from the s-in and gut lining, and from small daily losses of blood from the EI tract (=.( m, daily). Cumulatively, this amounts to $ mg of iron. 8ales with severe siderosis from blood transfusions can lose a ma3imum of ; mg daily via these routes without additional blood loss. ! woman loses about <== mg of iron with each pregnancy. 8enstrual losses are highly variable, ranging from $= to 7<= m, (;)$== mg of iron) per period. hese iron losses in women double their need to absorb iron in comparison to males. ! special effort should be made to identify and treat iron deficiency during pregnancy and early childhood

because of the effects of severe iron deficiency upon learning capability, growth, and development.

&ace$related demographics
Race probably has no significant effect upon the occurrence of iron deficiency anemia. however, because diet and socioeconomic factors play a role in the prevalence of iron deficiency, it more frequently is observed in people of various racial bac-grounds living in poorer areas of the world.

Prognosis
Iron deficiency anemia is an easily treated disorder with an e3cellent outcome. however, it may be caused by an underlying condition with a poor prognosis, such as neoplasia. 4imilarly, the prognosis may be altered by a comorbid condition such as coronary artery disease. "romptly and adequately treat a patient with iron deficiency anemia who is symptomatic with such comorbid conditions. Chronic iron deficiency anemia is seldom a direct cause of death. however, moderate or severe iron deficiency anemia can produce sufficient hypo3ia to aggravate underlying pulmonary and cardiovascular disorders. 6ypo3ic deaths have been observed in patients who refuse blood transfusions for religious reasons. @bviously, with bris- hemorrhage, patients may die from hypo3ia related to posthemorrhagic anemia. 2hereas a number of symptoms, such as ice chewing and leg cramps, occur with iron deficiency, the maFor debility of moderately severe iron deficiency is fatigue and muscular dysfunction that impairs muscular wor- performance. In children, the growth rate may be slowed, and a decreased capability to learn is reported. In young children, severe iron deficiency anemia is associated with a lower intelligence quotient (II), a diminished capability to learn, and a suboptimal growth rate.

Patient Education
"hysician education is needed to ensure a greater awareness of iron deficiency and the testing needed to establish the diagnosis properly. "hysician education also is needed to investigate the etiology of the iron deficiency. "ublic health officials in geographic regions where iron deficiency is prevalent need to be aware of the significance of iron deficiency, its effect upon wor- performance, and the importance of providing iron during pregnancy and childhood. he addition of iron to basic foodstuffs is employed in these areas to diminish the problem. 0or patient education resources, see the Blood and ,ymphatic 4ystem Center and the /sophagus, 4tomach, and Intestine Center, as well as !nemia and Celiac 4prue.